Viral coinfection promotes tuberculosis immunopathogenesis
by type I IFN signaling-dependent impediment of Th1 pulmonary influx
Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is often exacerbated upon coinfection, but the underlying immunological mechanisms remain unclear. Here, to elucidate these mechanisms, we used a Mtb and lymphocytic choriomeningitis virus coinfection model. Viral coinfection significantly suppressed Mtb-specific IFN-γ production, with elevated bacterial loads and hyperinflammation in the lungs. Type I IFN signaling blockade rescued the Mtb-specific IFN-γ response and ameliorated lung immunopathology. Single-cell sequencing, tissue immunofluorescence staining, and adoptive transfer experiments revealed that type I IFN signaling produced in response to viral infection inhibited CXCL9/10 production in myeloid cells, resulting in impaired pulmonary migration of Mtb-specific CD4+ T cells from lymph nodes. Thus, virus coinfection-induced type I IFN signaling prior to the pulmonary localization of Mtb-specific Th1 cells exacerbates TB immunopathogenesis by impeding the Mtb-specific Th1 cell influx. Our study highlights another novel negative role of viral coinfection and/or type I IFNs in delaying Mtb-specific Th1 responses in the lung.